Scleroderma/Systemic sclerosis (SSc) is a prototypic fibrotic disease that affects multiple organs including the skin and lung. Lung fibrosis is the leading cause of death in SSc patients. The hallmark of fibrosis is the disruption of extracellular matrix (ECM) homeostasis, with accumulation of ECM components and subsequent organ failure. However, the basic mechanisms responsible for the initiation and perpetuation of fibrosis are incompletely understood, which impedes the development of effective therapies. One of the hotly debated questions is the origin of fibrogenic cells. We identified an extensive population of pericytes in normal lung, defined by FoxD1 lineage tracing and pericyte marker expression. Our preliminary data, using genetic fate mapping, demonstrate that FoxD1 derived lung pericytes are a major source of myofibroblast progenitors following bleomycin-induced lung injury. However, whether pericytes are a major source of collagen and myofibroblasts in skin remains unexplored. We identified a peptide derived from endostatin, named E4, that is effective at reducing skin and lung fibrosis if given subcutaneously, intraperitoneally, or intratracheally. However, it is unclear whether E4 targets pericytes or pericyte-derived myofibroblasts in lung or skin, key myofibroblast progenitors. Our preliminary data suggests that E4 treatment of pericytes decreases markers of fibrosis. Understanding the relevant target cell type will be important in optimizing the translation of E4 to the clinic. Based on these findings we hypothesize that activated pericytes contribute to myofibroblast populations in both skin and lungs, and pericytes are an important target cell for the anti-fibrotic activities of E4. To investigate these hypotheses, we propose to: 1. Compare the role of lung and skin pericytes as myofibroblast progenitors in murine fibrosis models. 2. Compare the distribution and function of pericytes from lung and skin from normal and scleroderma patients. 3. Determine if lung and skin pericytes are a target of the novel anti-fibrotic peptide E4. If successful, our findings will have significant impact on our understanding of skin and lung fibrosis in SSc, a disease that remains incurable and facilitate the translation and development of an anti-fibrotic peptide.